Aspirin-Exacerbated Respiratory Disease (AERD), also referred to as Samter's Triad, is an immune-mediated inflammatory syndrome that affects 7% of adults with asthma and 14% of those with severe asthma. Patients with AERD develop asthma and severe chronic sinus disease with aggressive nasal polyposis that causes constant symptoms of nasal blockage and sinus pain, and a need for multiple surgeries to remove polyps is common. Patients with AERD also develop a hypersensitivity to aspirin and other inhibitors of cyclooxygenase-1. Ingestion of these medications elicits an acute, occasionally life-threatening, asthma attack accompanied by increasing nasal congestion, runny nose, and sometimes stomach pain and rash. Despite the morbidity from the syndrome and its frequency in the adult population of asthmatics, little is known about its etiology or underlying mechanisms. Existing data point to fundamental abnormalities in the metabolism and action of eicosanoids in AERD. The airways in AERD are hypersensitive to the bronchoconstrictor effects of cysteinyl leukotrienes (cysLTs), part of the eicosanoid family and cysLTs were thought to be the main effectors of aspirin-induced reactions. However, although CysLT1R antagonists and the 5-lipoxygenase inhibitor zileuton do alleviate some symptoms they are not uniformly effective and do not modify the chronic disease course. Moreover, high-dose aspirin therapy, the only medical therapy shown to modify the progression of the disease by decreasing the rate of polyp regrowth, has no effect on the production of cysLTs. Our group has recently shown that in addition to cysLTs, a urinary metabolite of prostaglandin D2 (PGD2), PGD-M, is higher in AERD compared to aspirin-tolerant asthmatic controls, and PGD-M further increases during aspirin-induced reactions, especially in subjects with the most severe clinical reactions. Given these findings, we hypothesize that 1) PGD2 is a crucial effector eicosanoid in AERD that contributes to both the chronic eosinophilic respiratory tissue inflammation and the severe hypersensitivity reactions that occur upon ingestion of aspirin and 2) the suppression of PGD2 generation by high-dose aspirin therapy prevents effector cell migration into the respiratory tract and thus underlies the mechanism of therapeutic benefit afforded by this therapy. To address our hypotheses we propose the following Aims: AIM 1: Define the contribution of PGD2 to the chronic disease state and the eosinophilic respiratory inflammation in patients with AERD. AIM 2: Determine the biologic and clinical consequences of acute PGD2 release during aspirin-induced reactions in AERD. AIM 3: Determine if the aspirin-induced suppression of PGD2 relates to the therapeutic benefit in patients with AERD. Completion of these aims, including both human studies and in vitro studies of patient material, will result in a more thorough understanding of the immunopathophysiologic role of PGD2 in the etiology of AERD and will provide insight into new ways of diagnosing and treating this syndrome.